The proposed studies are aimed at developing a new tumor immunotherapy by using isoaspartyl-modified peptides to break immune tolerance to "self" tumor antigens on breast cancer cells. Most tumor antigens have been characterized as normal, non-mutated self-peptides, linking the concepts of autoimmunity with the development of tumor immunity. Previous studies demonstrated that vaccination with xenogenic peptide antigens could overcome immune tolerance. We hypothesize that isoaspartyl-modified peptides can activate tumor reactive immune responses that lead to tumor reduction or elimination. This hypothesis is supported by our preliminary studies using a murine model of autoimmunity. Immunization with isoaspartyl-modified peptides generated cytotoxic (killer) T cells and humoral immune responses to "self antigens." The proposed studies will extend these observations to a transgenic mouse model of mammary tumors. We will immunize neu transgenic mice with isoaspartyl-modified peptides representing selected epitopes in the oncogenic HER-2/neu "self" tumor antigen. We will then examine tumor-specific immune responses, tumor regression, and histology in this genetic mouse mammary tumor model that resembles human breast cancer. Our long-term goal is to develop an isoapartyl-modified peptide vaccine that will overcome immune tolerance in breast cancer patients, and enhance pre-existing immunity to HER-2/neu to therapeutic levels.